African American (AA) men exhibit 1.6-fold higher incidence and 2.4-fold higher mortality rates from prostate cancer (PCa) compared to white men. Although much of this disparity remains after controlling for factors related to social determinants of health, very few studies have used this population-based difference to identify molecular mechanisms of tumor aggressiveness. The proposed work addresses the urgent need to interrogate the molecular mechanisms driving the more aggressive PCa biology in AA men across the PCa progression continuum and to modulate such mechanisms for therapeutic application. Our data from evaluating PCa biopsy tissue from AA and white patients has led to the discovery of alternative splicing as a novel molecular mechanism underlying more aggressive PCa in AA men. Preliminary analysis has indicated that several of these race-related alternative splicing events track with increased growth and more aggressive invasion characteristics of PCa in AA men. Additional preliminary work has demonstrated our capability to generate the first significant collection of PCa patient-derived explants and the first establishment of PCa patient-derived explants from AA patients. We aim to extend our preliminary findings by 1) determining the pattern and frequency of candidate race- related splice variants across the PCa progression continuum, from localized PCa of varying degrees of aggressiveness to metastatic castration-resistant PCa, and defining the relationship between these variants and PCa cell biology, 2) assessing the effects of expression of particular race-related splice variants on mechanistic and functional biology in population-specific PCa cell lines and developing tools to pharmacologically modulate race-related oncogenic splice variants for therapeutic application using AA and white PCa cell lines and AA and white PCa patient-derived explants generated for this study and 3) defining the biological significance of cis- acting splicing elements and/or trans-acting splicing factors to driving the alternative splicing events specific to AA PCa. The rationale for and impact of this study are that it will further our understanding of the molecular mechanisms driving PCa disparities and aid in development of novel precision biomarkers for prostate tumor aggressiveness and/or therapeutic agents against aggressive PCa. Such precision medicine interventions will reduce PCa disparities for AAs and will likely have impact on a subset of patients of all races with aggressive PCa. New AA and white PCa bio-specimens, AA and white PCa patient-derived explants and derivative cell lines and splicing-related materials and methods and tools resulting from the proposed work will be available to the nationwide cohort of scientists conducting research on PCa disparities.